The pyrimidine compound with which the present invention is concerned has the following structural formula ##STR1## and is known as buspirone. The hydrochloride salt has been referred to in the prior art as MJ 9022-1 and as buspirone hydrochloride. Other acid addition salts thereof are named by combining "buspirone" with the appropriate word to define the acid from which it is prepared as in "buspirone hydrochloride". The latter is the United States Adopted Name (USAN); refer to J. American Assoc. 225, 520 (1973).
The synthesis of the compound and the disclosure of its psychotropic properties are described in the following patents and publications.
1. Y. H. Wu, et al., J. Med. Chem., 15,477 (1972).
2. Y. H. Wu, et al., U.S. Pat. No. 3,717,634 which issued Feb. 20, 1973.
3. L. E. Allen et al., Arzneium. Forsch., 24, No. 6, 917-922 (1974).
4. G. L. Sathananthan, et al., Current Therapeutic Research. 18/5, 701-705 (1975).
5. Y. H. Wu, et al., U. S. Pat. No. 3,976,776, issued Aug. 24, 1976.
The following patent references disclose and claim additional uses that relate to buspirone's pharmacological effects on the central nervous system.
6. The use of buspirone hydrochloride as a novel antianxiety agent for the treatment of neurotic patients is described in G. P. Casten, et al., U. S. Pat. No. 4,182,763, issued Jan. 9, 1980.
7. Allen, et al., disclose the use of buspirone in treating extrapyramidal motor disorders in U.S. Pat. No. 4,438,119, issued Mar. 20, 1974.
8. Buspirone's use in sexual dysfunction was described by Othmer, et al., in U.S. Pat. No. 4,640,921, issued Feb. 3, 1987.
9. Kurtz, et al., in U.S. Pat. No. 4,634,703, issued Jan. 6, 1987 disclose buspirone's use in treating panic disorders.
10. Alderdice discloses the use of buspirone in the improvement of short term memory in U.S. Pat. No. 4,687,772, issued Aug. 18, 1987.
11. U.S. Pat. No. 4,777,173 of Shrotriya and Casten, issued Oct. 11, 1988 discloses and claims the use of buspirone in treating alcohol abuse.
There have also been several reports that buspirone has potential for use as a mixed anxiolytic-antidepressant agent (see, for example, Goldberg, et al., J. Clin. Psychiatry, 43/12 Part 2, pp 87-91 (1982)).
Reports of anxiolytic agents demonstrating some antidepressant properties are known, e.g. alprazolam, a benzodiazepine anxiolytic agent with some antidepressnt properties. This type of psychotropic profile has been considered to be of value since anxious patients often present with some symptoms of accompanying depression.
It is to be appreciated however that there are different types of depression, ranging from normal degrees of depressed mood, which is universally experienced, to major depressive illness, which is a condition of significant morbidity and mortality. The increasing severity of the differing types of depression, going from minor, or secondary, forms with partial or milder forms of depression to a major, more severe, primary depressive disorder is consonant with the increasing suffering and misery experienced by such patients and their families. Treatment of depression is complicated unfortunately as depressive illness is not a single entity but a heterogeneous group of disorders, comprised of several subtypes. It is important to realize that these subtypes involve different patient populations and may respond differently to antidepressant treatments. This is evidenced by the observation that about one-third of the patients in a typical treatment population are non-responders or respond only partially. Efforts have continued for years to improve differential diagnosis of the various subtypes of depression so that the most appropriate treatment may be employed. This is particularly important in view of the public health costs of depression and variability of response to treatment.
Adding further complexity to the selection of appropriate antidepressant treatment are differences in standardized diagnostic terminology. For example, the more severe major depressive disorder subtype, melancholia (DSM-III), has been variously classified as: "major affective disorder", "endogenous depression", "typical depression", "melancholic depression", "major depressive disorder", "primary depressive disorder" and "depressed phase of affective psychoses". This subtype of depressive illness is characterized by severe manifestations of depression, such as marked retardation or agitation, guilt, early morning awakening, diurnal variation of mood (worse in morning), loss of appetite. Response to electroconvulsive therapy and the tricyclic-class of antidepressant drugs is more predictably positive in this patient population.
A different serious primary depressive disorder subtype is classified as "atypical depression". The depressed patients comprising this subtype of depressive illness may be characterized by anxiety, phobic and histrionic symptoms, extreme sensitivity to rejection, emotional over-reactivity, being energetic and highly active when not depressed, but suffering fatigue, initial insomnia and reversed diurnal variation (mood worse at night) when depressed. This class of patient may sometimes score low on "depression" psychometric instruments, since its members may not display guilt, delusional ideas, severe weight loss, or suicidal intent and are not usually hospitalized for treatment. Because these patients respond poorly to electric convulsion therapy and standard antidepressant drug treatment, they present real difficulties and suffer much distress. The current treatment of choice employed for "atypical" depressives is administration of monoamine oxidase inhibitors (MAOI's), an older class of drugs that have more restricted usage due their inherent side-effects, not the least of which is the considerable risk due to food and drug incompatabilities with MAOI administration. All exposure to indirect acting sympathomimetic amines, particularly tyramine (found in red wine, aged cheeses, aged proteins, etc.) must be avoided in MAOI-treated patients. Many common over-the counter medicines must also be avoided including almost all cold medicines (nasal sprays as well), diet pills, antihistamines, some suppositories and so forth.
Melancholic depression, as well as other primary or major depressive disorders such as psychotic depression or atypical depression may be distinguished from minor depressive disorders and dysthymic states where anxiety with depressed mood may be prominent. These latter tend to be less severe depressive disorders. Also distinguishing these groups of patients is that different treatments are employed for each. Treatments standard for the primary depressive disorders such as tricyclic antidepressant agents, MAO inhibitors and electric convulsive shock, are less apt to be used to treat patients suffering from neurotic disorders with secondary depressive symptoms. These patients are usually treated by such treatment modalities as psychotherapy and/or antianxiety drug therapy. Similarly, treatment appropriate for mixed anxiety-depressive states is not usually effective in relieving the core depression symptoms of primary depressive disorders. While these observations may be used as an empirical guide in selecting an appropriate drug treatment, there is of course no way to predict success of drug therapy beforehand in each of these subtypes.
A pertinent consideration of prior art concerns gepirone, a novel anxiolytic agent with structural and pharmacological similarities to buspirone. Gepirone was disclosed as being useful in certain primary depressive disorders, including melancholic and atypical depression in U.S. Pat. No. 4,771,053, issued Sept. 13, 1988, to Cott, et al. In contrast, until the recent discovery marking the present invention, buspirone was not known to be particularly effective against primary depression, particularly in patients with melancholia where the drug had no effect. (cf: Schweizer, et al., Psychopharmacol. Bull., 22: 183-185 (1986).
The unexpected finding comprising the present invention is that buspirone is effective in treating severely affected patients suffering from primary depressive disorders, particularly major (endogenous) depression with melancholia. Prior teachings of the art suggested that buspirone was not useful in treating the more severe primary depressive illnesses, especially melancholic depression. The pharmacologic profile of buspirone as an anxiolytic agent with antidepressant properties indicated that buspirone could have usefulness in treating the minor, or secondary depression-anxiety subtype of patient. Drugs useful in treating secondary depression subtypes are not usually employed in treating primary depressive illnesses. In spite of continuing antidepressant drug development activity of the past twenty years, no anxiolytic agent with antidepressant properties has been approved by the FDA for effective treatment of severe primary depressive illnesses.
In summary, buspirone has demonstrated in double-blind, placebo-controlled studies that it is useful in the treatment of certain primary depressive disorders, particularly for more severely affected patients such as those with major depression of the melancholic subtype. It is now appreciated by those skilled in the art that depressive illness is comprised of distinguishable disease states with differently defined patient populations and drug responses. It is further appreciated that agents that are effective in treating one subtype of depression may be ineffective against other of the subtypes; i.e., it is not obvious beforehand if an agent will effectively alleviate a primary depressive disorder of any one clinical subtype. There existed nothing in the prior art that taught buspirone would be useful in alleviation of major depression with melancholia, as well as nonmelancholic depression and atypical depression.